tbuckley/cabot-search huggingface dataset:
Risk of second primary malignancies among patients with nasopharyngeal cancer in the United States: A population-based study.
Authors: Karthik Chamarti, Bibek Bakhati, Vasudha Rudraraju, Maneesh Mannem, Maryam Rajput, John Garza, Kelash Bajaj
Journal: Journal of Clinical Oncology (2022)

e18056 Background: Nasopharyngeal cancers (NPCs) have an estimated incidence of 0.5 to 2 cases per 100,000 in the United States. Treatment of NPC with combination chemoradiotherapy has resulted in an 18% increase in 5-year overall survival in the US. It is essential to focus on the developments of second primary malignancies (SPMs) with improved survival. We aim to analyze the risk of SPMs among NPC survivors in this study. Methods: We estimated the incidence of SPMs among two-month survivors of NPC using the Surveillance, Epidemiology, and End Results (SEER)-18 registries between 2006 to 2018. The risk of SPMs was calculated using standardized incidence ratios (SIRs). Results: We included 7,560 patients with NPC in this study. The median age of diagnosis was 56 yrs (range 0 to 85 yrs). The median follow-up duration was 33 months (range 0 to 155 months). The median time for SPM development from initial diagnosis was 41 months (range 2 to 140 months). A total of 367 (5%) patients developed 398 SPMs at the last follow-up, of which 89% were solid organ malignancies, and 11% were hematologic neoplasms. The SPM risk for cohort was significantly elevated (SIR = 1.88, 95% confidence interval [CI] = 1.7 to 2.07) compared with the general population. The SIR was slightly higher in males (SIR = 1.90, 95% CI = 1.69 to 2.13) compared to females (SIR = 1.81, 95% CI = 1.48 to 2.20). The SIR according to age groups were as follows: age &lt; 65 years (SIR = 2.03, 95% CI = 1.79 to 2.29), age &gt; 65 years (SIR = 1.65, 95% CI = 1.38 to 1.94). Sites with highest risk included the nose, nasal cavity, and middle ear (SIR = 22.98, 95% CI = 9.92 to 45.27), nasopharynx (SIR = 17.28, 95% CI = 8.93 to 30.19), oral cavity and pharynx (SIR = 10.07, 95% CI = 7.81 to 12.79), esophagus (SIR = 3.97, 95% CI = 1.9 to 7.29), lung and bronchus (SIR = 3.53, 95% CI = 2.86 to 4.32), and liver (SIR = 3.05, 95% CI = 1.86 to 4.71) (Table). The risk of malignancies of the esophagus and lung were higher within the first year of diagnosis of NPC. The risk of malignancies of the nasopharynx, oral and nasal cavity, and liver was higher after one year of latency and remained statistically significantly elevated throughout the follow-up period. Conclusions: Our study reveals that patients with NPC are at higher risk of SPMs than the general population, most notably in the oral and nasal cavity, nasopharynx, esophagus, and lungs. These patients may benefit from cancer-specific screening during follow-up.[Table: see text]
Role of anakinra in the management of icans after CAR T-cell therapy for lymphoma.
Authors: Nishant Munugala, Ulyana Dashkevych, Muhammad Husnain
Journal: Journal of Clinical Oncology (2022)

e19506 Background: Chimeric antigen receptor (CAR) T-cell immunotherapy is a revolutionary treatment modality which has gained attention for its potential in treating multiple refractory hematological malignancies. Significant toxicities associated with CAR T- cell therapy remain a major concern. Cytokine release syndrome (CRS) and Immune Effector Cell Associated Neurotoxicity Syndrome (ICANS) are seen early on post CAR-T cell therapy. To date, the treatment of ICANS has largely been limited to supportive care and corticosteroids. More recently, some early clinical data investigated the use of Anakinra as a promising agent in prevention and treatment of severe ICANS. Methods: We analyze three cases in which Anakinra was used to treat high-grade ICANS concurrently with high dose steroids. Results: A 51-year-old woman with high grade DLBCL and secondary CNS involvement was treated with Tisagenlecleucel CAR-T therapy. On day 2, patient became altered and was diagnosed with ICANS Grade II. High dose steroids were started leading to resolution of ICANS. However, patient’s mentation worsened by day 7, progressing to ICANS Grade IV by day 8, and Anakinra 100 mg IV was added to the steroid regimen. By day 11, after 4 doses of Anakinra, patient’s neurotoxicity completely resolved. Patient achieved a PR by day 30 after CAR-T cell infusion. In the second case, a 65-year-old man with DLBCL and leptomeningeal involvement developed ICANS Grade II on day 1 after Tisagenlecleucel CAR-T therapy and was started on high dose steroids. By day 4, neurotoxicity worsened and progressed to ICANS Grade IV. On day 5 patient was transferred to ICU for a mechanical ventilation, and Anakinra 100 mg IV was added and continued daily for 7 days. By day 12, neurotoxicity improved to ICANS grade II and patient was extubated. Meanwhile, high dose steroids were tapered. His condition acutely worsened by day 19, prompting transfer to the ICU and re-initiation of Anakinra concurrently with steroids. His family decided against further escalation of care on day 22. Patient was transitioned to comfort care and died 23 days post CAR-T cell infusion. In the third case, a 65-year-old man with mantle cell lymphoma was treated with Brexucabtagene autoleucel CAR-T therapy. On day 8, patient developed ICANS Grade I which rapidly progressed to Grade IV. High dose steroids were started and ICANS improved to Grade II on Day 9. However, on Day 10 patient’s mentation again worsened and one dose of Anakinra 100mg IV was added to the steroid regimen. By day 11, ICANS completely resolved, and patient was ultimately discharged home on day 15. Patient was able to achieve interval CR by day 30 after CAR-T cell infusion. Conclusions: In the reported cases, ICANS improved following administration of Anakinra, adding support to the idea that Anakinra may be beneficial in treatment of high-grade ICANS. Future studies are needed to better understand the overall efficacy and the ideal timeline for administration.
KITE-363: A phase 1 study of an autologous anti-CD19/CD20 chimeric antigen receptor (CAR) T-cell therapy in patients with relapsed/refractory (R/R) B-cell lymphoma (BCL).
Authors: Loretta J. Nastoupil, Saurabh Dahiya, David Bernard Miklos, Patrick Michael Reagan, Matthew Ulrickson, A. Scott Jung, Ioana Kloos, Jinghui Dong, Justin Chou, Jodi Murakami, Katherine Rodriguez, Myrna Nahas
Journal: Journal of Clinical Oncology (2022)

TPS7579 Background: One mechanism by which B-cell tumors can resist the effects of CD19-targeted CAR T-cell therapy is through CD19 antigen escape (Neelapu et al. ASH 2019). Recent analyses in large B-cell lymphoma (LBCL) demonstrated that approximately one-third to two-thirds of relapses after infusion of CAR T-cell therapy were CD19 negative (Plaks et al. Blood. 2021; Spiegel, Dahiya et al. Blood. 2021; Spiegel et al. Nat Med. 2021). KITE-363 is an autologous CAR T cell transduced with a bicistronic vector with resultant expression of a CD19 CAR with a CD28 costimulatory domain and a CD20 CAR with a 41BB costimulatory domain. In preclinical studies, KITE-363 recognized and eliminated tumor cells expressing CD19 and/or CD20. KITE-363 CAR T-cell therapy has the potential to rescue CD19-negative relapsing patients with BCL as well as prevent CD19 antigen escape by minimizing selective pressure through upfront therapeutic dual targeting. This Phase 1, first-in-human, open-label, multicenter study (NCT04989803) will evaluate the safety and preliminary efficacy of KITE-363 in patients with R/R BCL. Methods: The Phase 1 design includes a 3+3 dose-escalation portion (1A), with 5 planned CAR T-cell levels, and a dose expansion portion (1B). Patients may receive optional corticosteroid bridging therapy following leukapheresis. Patients will then receive conditioning chemotherapy (cyclophosphamide and fludarabine) on Day ‒5 to Day ‒3 followed by KITE-363 infusion on Day 0. The primary endpoint for Phase 1A is the incidence of adverse events defined as dose-limiting toxicities. The primary endpoint for Phase 1B is investigator-assessed objective response rate per Lugano criteria (Cheson et al. J Clin Oncol. 2014). Secondary endpoints include complete response rate, time to next treatment, duration of response, progression-free survival, overall survival, safety, and levels of CAR T cells in blood and cytokines in serum. Eligible adult patients have histologically confirmed BCL, including LBCL, indolent non-Hodgkin lymphoma, nodular lymphocyte-predominant Hodgkin lymphoma (HL), and BCL, unclassifiable (with features intermediate between diffuse LBCL and classical HL), that is R/R after ≥2 lines of therapy (patients with LBCL may have primary refractory disease). Other key inclusion criteria are adequate bone marrow and organ function and ECOG performance status 0‒1. Key exclusion criteria are central nervous system (CNS) involvement from lymphoma, active infection including hepatitis B and C, and clinically significant CNS disorder. This study is currently open and accruing patients. Clinical trial information: NCT04989803.
A collaborative model for continuing medical education: Impact of a distance learning curriculum for existing radiation oncology centers in Africa and Latin America.
Authors: Meridith Leigh Balbach, Grantly Neely, Afua Adutwumwaa Yorke, Evangelina Figueroa Medina, Jonathan Judd Paly, Rebecca Maria Shulman, William B. Cutrer, Li Benjamin
Journal: Journal of Clinical Oncology (2022)

11007 Background: We aimed to evaluate the outcomes and generalizability of a distance learning curriculum on intensity modulated radiotherapy (IMRT), a course developed for radiotherapy clinics across Africa and Latin America (LATAM) at no cost, as measured by a knowledge-based multiple-choice exam, learner self-evaluation, and open-ended feedback. Methods: Following needs identification studies, a curriculum entitled “IMRT 2.0” was created for an audience that included medical physicists, radiation oncologists, radiation therapists, and trainees. Volunteer educators delivered 27 hour-long sessions 1-2 times weekly for four months using video conferencing to African and LATAM programs in English and Spanish, respectively. Recordings and educational materials were shared following each session. Pre- and post-course multiple choice examinations were administered to LATAM participants, and pre- and post-course Likert scale self-evaluation and open-ended feedback were collected for both programs. Paired sample t-tests and chi-squared tests were performed for all available paired quantitative and categorical data, respectively. Pearson correlation coefficient, multivariate linear regression, and spline regression models were used to explore impact of course attendance on outcomes. Results: 25 centers across Africa (12 + 1 sister institution in Pakistan) and LATAM (12) were recruited, the majority (92%) of which were recently transitioning or planning to transition to IMRT, yielding a total of 332 enrolled participants. 27 sessions were delivered with a mean of 44 (std dev 22.5) and 85 (std dev 25.4) participants per session for the African and LATAM programs, respectively. Paired pre- and post-course data demonstrated significant improvement in both knowledge (n = 51, p &lt;.001) and overall self-confidence (n = 85, p &lt;.001). Synchronous participation did not predict greater score improvement or increase in self-confidence. Thematic analysis suggests that participants found great value in this course and look forward to future learning. Conclusions: A volunteer-driven course on IMRT is generalizable across regions in different languages and serves as an effective hub to arm participating centers with the knowledge and confidence they need to enhance patient care at their institutions. This benefit may propagate as participants become the next generation of trainers. Other fields and specialties aiming to reduce global health care disparities through training efforts could consider adopting this approach.
A Transcriptomic Atlas Underlying Developmental Plasticity of Seasonal Forms of <i>Bicyclus anynana</i> Butterflies
Authors: Shen Tian, Antónia Monteiro
Journal: Molecular Biology and Evolution (2022)

Abstract Organisms residing in regions with alternating seasons often develop different phenotypes, or forms, in each season. These forms are often adaptations to each season and result from an altered developmental response to specific environmental cues such as temperature. Although multiple studies have examined form-specific gene expression profiles in a diversity of species, little is known about how environments and developmental transitions, cued by hormone pulses, alter post-transcriptional patterns. In this study, we examine how gene expression, alternative splicing, and miRNA-mediated gene silencing in Bicyclus anynana butterfly hindwing tissue, varies across two rearing temperatures at four developmental timepoints. These timepoints flank two temperature-sensitive periods that coincide with two pulses of the insect hormone 20E. Our results suggest that developmental transitions, coincident with 20E pulses, elicit a greater impact on all these transcriptomic patterns than rearing temperatures per se. More similar transcriptomic patterns are observed pre-20E pulses than those observed post-20E pulses. We also found functionally distinct sets of differentially expressed genes (DEGs) and differentially spliced genes (DSGs) in the seasonal forms. Furthermore, around 10% of DEGs are predicted to be direct targets of, and regulated by, differentially expressed miRNAs (DEmiRs) between the seasonal forms. Many DEGs, DEmiRs, or DSGs potentially regulate eyespot size plasticity, and we validated the differential splicing pattern of one such gene, daughterless. We present a comprehensive and interactive transcriptomic atlas of the hindwing tissue of both seasonal forms of B. anynana throughout development, a model organism of seasonal plasticity.
The impact of EGFR Exon 20 mutation subtypes on lung cancer prognosis.
Authors: Ming Xu, Yingmei Li, Danni Liu, Tianhao Mu, Nitao Cheng
Journal: Journal of Clinical Oncology (2022)

e20557 Background: Many lung cancer patients with epidermal growth factor receptor (EGFR) mutations benefit from tyrosine kinase inhibitors (TKIs). However, patients with EGFR exon 20 mutations usually have worse response rates than other types of EGFR mutations. Here we investigated how different mutation subtypes of EGFR exon 20 affected the prognosis. Methods: Clinical and genomic data from 3 studies (MSKCC2020, MSKCC2021, and OncoSG) of patients with lung adenocarcinoma (LUAD) were reviewed (n = 1,001). Four hundred and seventeen patients harbored EGFR mutations and 52 of them had EGFR exon 20 mutations. The correlation of mutation subtypes with OS data was analyzed using R package. Results: In lung cancer patients with EGFR mutations (n = 417), 52 of them (12.5%) had a total of 64 EGFR exon 20 mutations, and could be categorized into 16 different subtypes, with top 5 subtypes being T790M (n = 28), S768I (n = 8), C797S (n = 7), A767_V769dup (n = 6) and S768_D770dup (n = 3). Patients with S768I (p = 0.0038) and A767_V769dup (p = 0.03) were found to have significantly worse OS than patients without these mutations by log-rank test. EGFR T790M, which was the most prevalent exon 20 mutation in these patients, did not present significant correlation in survival analysis. Conclusions: Although patients with EGFR exon 20 mutations accounted for only about 5% LUAD patients, and had worse response rates in general, certain subtypes had significantly different prognoses compared with other subtypes.
Daratumumab carfilzomib lenalidomide and dexamethasone as induction therapy in high-risk, transplant-eligible patients with newly diagnosed myeloma: Results of the phase 2 study IFM 2018-04.
Authors: Cyrille Touzeau, Aurore Perrot, Cyrille Hulin, Salomon Manier, Margaret Macro, Denis Caillot, Lionel Karlin, Olivier Decaux, Caroline Jacquet, Mourad Tiab, Xavier Leleu, Lucie Planche, Herve Avet-Loiseau, Philippe Moreau
Journal: Journal of Clinical Oncology (2022)

8002 Background: High-risk (HR) cytogenetic is associated with poor outcome in transplant eligible (TE) newly diagnosed myeloma multiple myeloma (NDMM). The triplet combination carfilzomib lenalidomide and dexamethasone (KRD) plus transplantation demonstrated high efficacy with favorable safety profile in TE-NDMM patients (FORTE). The addition of daratumumab (Dara) to frontline therapy also improved response rate and progression free-survival in TE-NDMM patients (CASSIOPEIA, GRIFFIN). Double transplant also improved outcome of HR TE NDMM patients (EMN02, STAMINA). The phase 2 trial 2018-04 from the Intergroupe Francophone du Myelome (IFM) is evaluating an intensive strategy with Dara-KRD induction and consolidation plus double transplant in HR TE NDMM (NCT03606577). Methods: HR MM was defined by the presence of del17p, t(4;14) and/or t(14;16). Stategy includes Dara-KRD induction (6 cycles), autologous stem cell transplantation (ASCT), Dara-KRD consolidation (4 cycles), second ASCT, Dara-lenalidomide maintenance. The primary endpoint was the feasibility of this intensive strategy. Here, we report efficacy and safety analysis of Dara-KRD induction. Results: Fifty patients with previously untreated NDMM were included from july 2019 to march 2021 in 11 IFM centers Median age was 57 (range 38 -65). ISS stage 3 was present in 12 (24%) patients. Based on inclusion criteria, all patients had HR cytogenetic, including 17p deletion (n = 20, 40%), t(4;14) (n = 26, 52%) or t(14;16) (n = 10,20%). Forty-six patients completed Dara-KRD induction. Two patients discontinued treatment due to severe adverse event (COVID-19 infection, n = 1 ; drug-induced hepatitis, n = 1) and 2 patients discontinued treatment due to disease progression. Grade 3-4 treatment related adverse event ( &gt; 5% of patients) were neutropenia (38%), anemia (14%), thrombocytopenia (8%), infection (6%), renal insufficiency (6%) and deep-vein thrombosis (6%). Two patients (6%) experienced stem-cell collection failure. Overall response rate was 96%, including 92 % &gt; very good partial response. Among 37 (/46) evaluable patients post induction, Minimal Residual Disease negativity rate (NGS, 10- 5 ) was 62%. Conclusions: Dara-KRD as induction prior ASCT is safe and allows deep responses in TE NDMM patients with high-risk cytogenetic profile. IFM 2018-04 study is ongoing and longer follow-up is needed to evaluate safety and efficacy of the overall strategy with Dara-KRD induction and consolidation plus double transplant in this subset of HR patients. Clinical trial information: NCT03606577.
Characterizing node-negative non-small cell lung cancer patients with similarity networks: A CancerLinQ Discovery analysis.
Authors: Erika L Moen, Zoe Chen, Andrew Schaefer, Alisha Bhimani, James O'Malley, Konstantin H. Dragnev
Journal: Journal of Clinical Oncology (2022)

e20585 Background: Patients with node-negative non-small cell lung cancer (NSCLC) whose tumors are completely resected account for approximately 17% of all patients with lung cancer, and disease recurrence occurs in approximately 1 in 5 of these patients. The lack of consensus on factors associated with risk of disease recurrence among node-negative NSCLC patients is a significant barrier to applying precision medicine strategies in this patient population. Clustering similar patients based on distances between various features of data is an emerging topic in precision medicine. Patient similarity networks represent a new model for clustering patients based on heterogeneous data, whereby any data type is converted into a similarity network by defining a similarity measure. The objective of this study was to examine the utility of patient similarity networks to identify NSCLC patients at higher risk of adverse outcomes. Methods: We conducted a retrospective, observational study of 6,020 node-negative NSCLC patients with an initial diagnosis in 2011-2014 in the CancerLinQ Discovery database. A patient similarity network was assembled based on comorbidities and network communities of patients with similar comorbidities at diagnosis were identified. Using Cox proportional-hazards modeling, we examined the extent to which patient age, sex, race, ethnicity, and network community predicted 2-year disease recurrence and 2-year mortality. Results: In the adjusted analyses, patients in the network community enriched for renal disease and congestive heart failure had an 83% increased risk of mortality (95% CI = 1.39-2.41). Patients in the network community enriched for pulmonary disease had a 37% increased risk of mortality (95% CI = 1.06-1.74) yet a lower risk of recurrence (HR = 0.5, 95% CI = 0.34-0.75). After adjusting for comorbidity network community, male patients had a 14% increased risk of mortality (95%CI = 1.02-1.28) and a 21% increased risk of recurrence (95% CI = 1.05-1.40) and black patients had a lower mortality risk (HR = 0.71, 95% CI = 0.58-0.86). Conclusions: Future studies applying patient similar networks to integrate additional diverse and high dimensional data types may afford more clarity in assigning risk of adverse outcomes.
B-catenin mutations and the response of advanced hepatocellular carcinoma to immune checkpoint inhibitors.
Authors: Himil Mahadevia, Robin John Lester Imperial, Beau Toskich, Kabir Mody
Journal: Journal of Clinical Oncology (2022)

e16124 Background: Immune checkpoint inhibitors (ICI) have emerged as a standard treatment option for advanced hepatocellular carcinoma (HCC). Unfortunately, many patients with advanced HCC develop progressive disease on ICI therapy. Furthermore, clinical predictors of response to ICI therapy in HCC are poorly understood. B-catenin mutations are among the most frequent genetic abnormalities in HCC and may provide a mechanism for immune evasion and poor response to ICI (Ruiz de Galarreta, Marina et al. “β-Catenin Activation Promotes Immune Escape and Resistance to Anti-PD-1 Therapy in Hepatocellular Carcinoma.” Cancer discovery 9,8 (2019): 1124-1141. doi:10.1158/2159-8290.CD-19-0074). Methods: We conducted a retrospective cohort study of patients with advanced HCC who were treated with ICI therapy. All patients had ctDNA tumor profiling and were assessed for B-catenin mutation status. Disease status was determined by RECISTv1.1. Median progression-free survival (PFS), 3-month PFS, 6-month PFS, and the disease control rate (DCR) on ICI therapy were compared between B-catenin mutation (BCM) and B-catenin wild-type (BCWT) groups. Results: 15 stage III/IV HCC patients were included in the study. 9 patients harbored BCMs and 6 patients were BCWT. The median PFS in patients with BCM HCC was 4.0 months versus 4.9 months in patients with BCWT HCC. At 3 months, PFS was 56% for BCM HCC compared to 67% for BCWT HCC. Furthermore, the 6-month PFS was 11% for BCM HCC and 50% for BCWT HCC. For best response, 33% of patients with BCM HCC achieved stable disease compared to 67% of patients with BCWT HCC. No patients in our cohort achieved partial or complete response. The DCR for BCM HCC was 33% and the DCR for BCWT HCC was 67%. Conclusions: In patients with advanced HCC, B-catenin mutation status may serve as a potential biomarker of response to ICI therapy. Our data suggests that patients who do not harbor these mutations, have a more durable response to ICI therapy. Further studies are needed to validate these findings.